This invention relates generally to block and graft copolymers, and more specifically, to block and graft copolymers which are effective in drug delivery, including copolymer-drug mixtures for the delivery and controlled release of a drug by topical application.
The effective and efficient delivery of a therapeutic drug to a patient is a goal of pharmaceutical science. Targeted drug delivery, such as topical application of a therapeutic drug to a site of action, has many advantages over systemic drug delivery. Typically, adverse side effects associated with systemic delivery may be greatly reduced when a therapeutic drug is delivered locally to the site of action by topical administration. Therapeutic drugs which are systemically administrated are dispersed relatively non-selectively throughout the patient""s body and metabolized, thus reducing their therapeutic effectiveness with respect to dosage, as well as increasing the likelihood of adverse reaction. In contrast, an effective dosage of a topically administrated therapeutic drug is often significantly less than that required through systemic administration. The diminution of dosage accompanying topical administration reduces the possibility of adverse reaction to the drug. In addition, drug metabolism of topically administered therapeutics is also minimized, thereby increasing their effectiveness.
While advantageous to systemic delivery, topical administration of a therapeutic drug is far from ideal. Perhaps the greatest single drawback to topical drug administration is the actual delivery of the therapeutic drug to the tissue to be treated. The absorption of the therapeutic drug by the tissue is often a slow process, and therefore requires a relatively long contact time between the tissue and the topical formulation containing the therapeutic drug. For example, topical administration of solutions of therapeutic drugs can be rather problematic. The use of viscous solutions, gels, ointments, lotions, patches, and inserts containing therapeutic drugs is a routine alternative to the administration of therapeutics in solution. These alternative formulations serve to enhance the contact time between the therapeutic drug and the tissue to be treated, thereby increasing the effectiveness of the topical treatment.
Ophthalmic drug delivery presents unique problems. Traditionally, eyedrops are the preferred mode of topical delivery of therapeutic drugs to the eye. Indeed, solutions of therapeutic drugs are routinely administered by this technique. However, it is well known that a major loss of drugs administered to the eye is via the lacrimal drainage system. This drainage is so effective that only a small fraction of the therapeutic drug remains in contact with the eye for any extended period of time. Consequently, topical delivery of therapeutic drugs to the eye via an eyedrop solution is relatively ineffective and requires repetitive treatments. The usual alternatives to the administration of solutions, such as the use of ointments and lotions to prolong tissue contact, are not particularly suitable for drug administration to the eye. Ointments and lotions are physically difficult to administer to the eye, and drug dosage is therefore difficult to control. The use of solid inserts has also been utilized to deliver therapeutic drugs to the eye. While this technique does assure a slow, effective release of the drug, patients often experience difficulty in placing and removing the insert into the cul-de-sac of the eye.
An alternative approach to ophthalmic drug delivery is the use of therapeutic drug formulations which are liquids at room temperature and which are transformed into gels upon warming through contact with tissue. These formulations, deliverable to the eye as liquid drops, may be readily dispensed and their dosage controlled. More significantly, once the liquid formulation is transformed into a gel on the surface of the eye, drainage of the therapeutic drug is retarded and its residence time on the eye is prolonged. The gelling of these formulations is attributable to polymer components which undergo solution-to-gel transitions in response to relatively small changes in environmental conditions (also called xe2x80x9ctriggersxe2x80x9d), such as temperature or pH. Polymers which undergo solution-to-gel transition upon changes in temperature are often referred to as xe2x80x9cthermally gelling polymersxe2x80x9d or xe2x80x9ctemperature-sensitive polymers.xe2x80x9d Similarly, polymers which undergo solution-to-gel transition as a result of a change in pH are generally referred to as xe2x80x9cpH-sensitive polymers.xe2x80x9d
Temperature-sensitive polymers which form gels upon warming undergo a solution-to-gel transition at their lower critical solution temperature (xe2x80x9cLCSTxe2x80x9d), also referred to as the xe2x80x9ccloud point.xe2x80x9d The formation of the gel is believed to result from the gathering of portions of the temperature-sensitive polymers into hydrophobic micro-domains which are maintained in the aqueous gel phase by the hydrophilic portion of the polymer. Such temperature-sensitive polymers, although water soluble at low temperature, generally possess some hydrophobic character. The polymer""s hydrophobic character is imparted by part of the monomer or repeat unit from which the polymer is derived. For example, poly(N-isopropylacrylamide) (xe2x80x9cNIPAAmxe2x80x9d) is well known to change its structure in response to temperature in aqueous solutions (see, e.g., Heskins et al., J. Macromol. Sci. Chem. A2, 1441-45, 1968). At temperatures below the LCST of NIPAAm (i.e., 32xc2x0 C.), polymer chains of NIPAAm hydrate to form an expanded structure, while at temperatures above the LCST the chains form a compact structure which excludes water. Thus, gel formation is due to the association of the relatively hydrophobic isopropyl groups of the NIPAAm polymer.
Temperature-sensitive polymers have been employed as vehicles for ophthalmic drug delivery. For example, block copolymers of ethylene oxide and propylene oxide have been disclosed in U.S. Pat. No. 4,188,373 for this purpose. However, in this system, the concentration of the polymer must be adjusted to provide the desired solution-to-gel transition temperature. The drawback to this system is that in order to achieve a solution-to-gel temperature suitable for gelling at body temperature, the polymer must be present at a relatively low concentration. Thus, the ability to obtain a gel with the desired properties is limited by the desired physiologically useful temperature range. The necessity for a low polymer concentration, in turn, limits the amount of drug that may be administered by such a polymer system.
Polymers which are sensitive to changes in pH, such as polyacrylic acid (xe2x80x9cpolyAAcxe2x80x9d), have also been utilized to form gels in situ, including use as vehicles in ophthalmic compositions. For example, U.S. Pat. No. 4,888,168 discloses a composition containing the homopolymer polyAAc, and gel formation occurs upon the subsequent addition of an acidic component. Gel formation results in this case by an increase in viscosity associated with the protonation of the carboxylic acid groups at low pH. In water at neutral pH, the carboxy groups of polyAAc are ionized and the polymer is a liquid-in-water solution. Lowering the pH to 4.3-4.5 by the addition of an acid, such as citric acid, results in gel formation due to formation of H-bonded crosslinks between xe2x80x94COOH groups. An undesirable limitation of this system for use as an ophthalmic drug delivery vehicle is that gel formation requires sequential addition of two solutions (i.e., a first polyAAc solution and a second acid solution). In addition, the pH of such an acid solution is undesirable to the eye.
Due to the drawbacks of existing temperature-sensitive and pH-sensitive polymers to provide suitable vehicles for topical drug delivery, researchers have studied random copolymers containing these components for use as a vehicle for topical drug delivery. Such random copolymers, however, have not proved suitable for physiological application. In particular, random copolymers of temperature-sensitive and pH-sensitive monomers quickly lose their temperature sensitivity upon increasing the content or ratio of the pH-sensitive monomers relative to the temperature-sensitive monomers. Thus, by employing a ratio of the pH-sensitive component sufficient to impart pH sensitivity to the random copolymer, such a ratio destroys the temperature sensitivity sought by incorporation of the temperature-sensitive components. In addition, cross-linking such random copolymers to form a hydrogel does not alleviate the problem. For example, cross-linked hydrogels of a random copolymer of acrylic acid (xe2x80x9cAAcxe2x80x9d) and NIPAAm, when used as a vehicle for drug delivery, releases the drug at a more rapid rate as the AAc content of the random copolymer is increased (Dong and Hoffman, J. Controlled Release 15:141-152, 1991).
Similarly, attempts have been made to employ aqueous solutions containing a mixture of temperature-sensitive and pH-sensitive polymers for ophthalmic drug delivery. Such mixtures, however, have also been met with only limited success. For example, U.S. Pat. No. 5,252,318 is directed to physical mixtures of temperature-sensitive and pH-sensitive reversibly gelling polymers. At physiological temperature and in buffered saline, such physical mixtures, when used for drug delivery, tend to separate as the temperature-sensitive polymer precipitates and the pH-sensitive polymer ionizes. Thus, such polymer mixtures are largely ineffective due to loss of drug through drainage from the eye.
Despite the advantages associated with the use of gel-forming polymers as vehicles for topical ophthalmic drug delivery, limitations to their utility persist. As mentioned above, these formulations are delivered as solutions and are thus susceptible to drainage from the eye before gel formation can be effected. Accordingly, there is a need in the art for a simple, dosage reliable, topically administrable composition which provides for delivery of a therapeutically effective amount of a drug which does not suffer rapid drainage from the treatment area. In addition, there is a need in the art for methods relating to the use of such compositions for topical drug delivery. The present invention fulfills these needs, and provides further related advantages.
In brief, environmentally-sensitive block and graft copolymers are disclosed. The environmentally-sensitive copolymers of this invention respond to environmental changes in, for example, temperature, pH, pressure, light, solvent or solvent concentration and ions or ionic strength. Accordingly, the environmentally-sensitive polymers of this invention include pH-sensitive, temperature-sensitive, pressure-sensitive, photo-sensitive, solvent-sensitive, solvent concentration-sensitive, ion-sensitive and ionic strength-sensitive polymer components. Such copolymers are particularly useful as vehicles for the controlled release of therapeutic drugs. In one embodiment, this invention is directed to graft copolymers comprising a backbone pH-sensitive polymer component with a pendant temperature-sensitive polymer component grafted thereto, or a backbone temperature-sensitive polymer component with a pendant pH-sensitive polymer component grafted thereto. In either case, the graft copolymers may have a lower solution critical temperature (xe2x80x9cLCSTxe2x80x9d), a melting temperature or glass transition temperature (collectively referred to herein as xe2x80x9ca critical temperaturexe2x80x9d) ranging from 20xc2x0 C. to 40xc2x0 C. at physiological pH.
In a related embodiment, there is disclosed block copolymers comprising a pH-sensitive polymer component and a temperature-sensitive polymer component joined thereto. As with the graft copolymers, the block copolymers of this invention may also have a critical temperature ranging from 20xc2x0 C. to 40xc2x0 C. at physiological pH.
The pH-sensitive polymer component of the block and graft copolymers preferably comprises a polymer which has bioadhesive properties, such as a carboxylic acid-containing polymer component derived from polymerizable carboxylic acids (such as acrylic acid and methacrylic acid), and preferably are either homopolymers or copolymers containing only a limited quantity of comonomer. The temperature-sensitive polymer component preferably has critical temperature ranging from 20xc2x0 C. to 40xc2x0 C. at physiological pH, and may be a homopolymer or a random or block copolymer. The pH-sensitive or temperature-sensitive polymer components may also be lightly cross-linked, resulting in cross-linked block and graft copolymer hydrogels.
In another embodiment, the present invention is directed to a physical mixture of a block or graft copolymer or hydrogel with a pharmaceutically acceptable drug to form a copolymer-drug mixture. For topical application to a treatment area, the copolymer-drug mixture is applied as a solid particle suspended in a pharmaceutically acceptable carrier. Alternatively, the copolymer may be dissolved in a pharmaceutically acceptable carrier in combination with the pharmaceutically acceptable drug and applied as a liquid copolymer-drug mixture. Upon contact with the treatment area, the copolymer of the copolymer-drug mixture forms a gel. Thus, this invention also discloses compositions containing particles of the copolymer-drug mixture suspended in a pharmaceutically acceptable carrier, as well as compositions containing the copolymer and drug in combination with a pharmaceutically acceptable carrier. In yet a further embodiment, there are disclosed methods for topically delivering a drug to a treatment area by administering such a composition thereto.
In yet a further embodiment, a block or graft copolymer may be lightly cross-linked to form a hydrogel. Suitable graft copolymer hydrogels comprise a backbone bioadhesive or pH-sensitive polymer component with a pendent temperature-sensitive component grafted thereto, or a backbone temperature-sensitive component with a pendent bioadhesive or pH-sensitive component grafted thereto. In addition, block copolymer hydrogels are also disclosed comprising a bioadhesive or pH-sensitive polymer component joined to a temperature-sensitive polymer component. Such hydrogels may contain one or more pharmaceutically acceptable drugs in, for example, a dissolved or dispersed form.
In yet another embodiment, there is disclosed a graft copolymer in which both the backbone and pendant polymer components are temperature-sensitive polymer components. Such graft copolymers may also have a critical temperature ranging from 20xc2x0 to 40xc2x0 C. and are useful for the controlled release of therapeutic drugs.
In still another embodiment, a graft copolymer hydrogel in which both the backbone and pendant polymer components are pH-sensitive polymer components is disclosed. These hydrogels are also useful for the delivery of therapeutic drugs.
In a further embodiment, graft and block copolymers having photosensitive polymer components are disclosed. In these copolymers, photosensitive moieties are incorporated into the copolymer such that the copolymer undergoes light induced phase transition. Such copolymers are useful in therapeutic drug delivery.
In yet a further embodiment, there are disclosed pressure-sensitive copolymers useful in adhesive applications. The pressure-copolymers undergo amorphous (adhesive) to crystalline (non-adhesive) phase transitions as a function of temperature and as such as temperature-sensitive copolymers. These copolymers are graft copolymers having long carbon chain pendant polymer components.
Still a further aspect of this invention involves block or graft copolymers (including hydrogels of the same) for general industrial use, including, for example, use as lubricants, moisturizers, bulk-formers and/or absorbents. In this context of the present invention, the block and graft copolymers may used over a wide pH and temperature range.
Other aspects of the present invention will become evident upon reference to the attached figures and following detailed description. To this end, various references are noted herein which are hereby incorporated by reference in their entirety.